Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis.
BACKGROUND
Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic growth factor that stimulates proliferation and migration of endothelial cells (ECs) via the c-Met receptor, present on ECs as well as other cell types, including smooth muscle cells (SMCs). We studied the effects of recombinant human (rh) SF/HGF in vitro and in vivo in a rabbit model of hindlimb ischemia. We further compared these effects with those of recombinant human vascular endothelial growth factor (rhVEGF165), an EC-specific mitogen.


RESULTS
In vitro, rhSF/HGF and rhVEGF165 exhibited similar effects on proliferation and migration of ECs. When both cytokines were administered together, the result was an additive effect on EC proliferation and a synergistic effect on EC migration. Application of rhSF/HGF to cultures of human SMCs resulted in the induction of VEGF mRNA and protein. In vivo, administration of rhSF/HGF (500 microg x 3) was associated with significant improvements in collateral formation (P<.001) and regional blood flow (P<.0005) and with a significant reduction in muscle atrophy (P<.0001). These effects were significantly more pronounced than those of rhVEGF165 administered according to the same protocol (P<.05). Neither remote angiogenesis nor other pathological sequelae were observed with either rhSF/HGF or rhVEGF165.


CONCLUSIONS
The pleiotropic effects of certain growth factors may potentiate angiogenesis via a combination of direct effects on EC proliferation and migration and indirect effects that result in the generation of other potent EC mitogens from non-EC populations. The synergistic effects demonstrated when SF/HGF and VEGF are administered together in vitro may be reproduced in vivo by SF/HGF-induced upregulation of VEGF in vascular SMCs.
Van Belle
E
E
Department of Medicine (Cardiology), St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Witzenbichler
B
B
Chen
D
D
Silver
M
M
Chang
L
L
Schwall
R
R
Isner
J M
JM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003097:Collateral Circulation / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007083:Iliac Artery / Q000187:drug effects / Q000503:physiopathology; D007511:Ischemia / Q000503:physiopathology*; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins; D012039:Regional Blood Flow / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017228:Hepatocyte Growth Factor